Certain methylene phosphonoalkylphosphinate compounds are disclosed in the following references: Gilmore, W. F., & J. W. Huber, "Base-Catalized Condensation of Aldehydes with Ethyl Bis(diethylphosphonomethyl)phosphonate", Journal of Organic Chemistry, Volume 38, No. 7 (1973), pp. 1423-1424; Gilmore, W. F., & J. S. Park, "Base-Catalized Condensation of Bis(diethylphosphonomethyl)phosphinic Amides with Aldehydes", Phosphorus and Sulfur, Volume 29 (1987), pp. 287-292; Aboujaoude, E. E., N. Collignon & P. Savignac, "Synthesis of Beta-carbonyl Phosphinates", Journal of Organometallic Chemistry, Volume 264 (1984), pp. 9-17; Henning, H. G., & G. Petzold, "Methylene-bis-phosphonic Acid Ester and Methylene-bis-phosphinic Acid Ester", Z. Chem., Volume 5, No. 11 (1965), pp. 419-420; Abramov, V. S., & V. I. Barabanov, "Reaction of Phosphinic Acids with Aldehydes and Ketones, XXVII." Zhurnal Obshchei Khimii, Volume 36, No. 10 (1966), pp. 1830-1834; Abramov, V. S., V. I. Barabanov & L. I. Long, "Reactions of Phosphinic Acids with Aldehydes and Ketones, XXXII." Zhurnal Obshchei Khimii, Volume 37, No. 3 (1967), pp. 714-718; Pudovik, A. N., I. V. Gur'yanova, L. V. Banderova & M. G. Limin, "Reaction of Partial Esters of Ethylphosphinic and Phosphorothioic Acids with Alpha-oxo Phosphonic Acid Esters and Diacetyl", Zhurnal Obshchei Khimii, Volume 37, No. 4 (1967), pp. 876-881; Pudovik, A. N., I. V. Gur'yanova & M. G. Zimin, "Reactions of Phosphorus Acid, Ethylphosphinic Acid, and Thiophosphorus Acid Esters with some Substituted Benzoyl Phosphates", Zhurnal Obshchei Khimii, Volume 37, No. 11 (1967), pp. 2580-2585; Pudovik, A. N., I. V. Gur'yanova, L. V. Banderova & G. V. Romanov, "Phosphonatephosphate Rearrangement of Esters of Alpha-hydroxyalkylphosphonic Acids", Zhurnal Obshchei Khimii, Volume 38, No. 1 (1968), pp. 143-150; Pudovik, A. N., G. E. Yastrebova, V. I. Nikitina & Y. Y. Samitov, "Synthesis and Reactions of Esters of (Beta-cyanovinyl)phosphonic Acid", Zhurnal Obshchei Khimii, Volume 38, No. 2 (1968), pp. 292-299; Romanov, G. V., M. S. Yafarov, A. I. Konovalov, A. N. Pudovik, I. V. Konovalova & T. N. Yusupova, "Thermodynamic and Kinetic Characteristics of the Phosphonate-phosphate Rearrangement", Zhurnal Obshchei Khimii, Volume 43, No. 11 (1973), pp. 2378-2386; Novikova, Z. S., S. N. Mashoshina & I. F. Lutsenko, "Addition of Tetraethyl Pyrophosphite and Tetraethyl Isohypophosphate to Compounds with Activated Multiple Bonds", Zhurnal Obshchei Khimii, Volume 44, No. 2 (1974), pp. 276-281; Novikova, Z. S., A. A. Prishchenko & I. F. Lutsenko, "Synthesis of 1,3-Di(oxoalkoxyphospha)cycloalkanes", Zhurnal Obshchei Khimii, Volume 47, No. 11 (1977), pp. 2636-2637; Novikova, Z. S., S. Y. Skorobogatova & I. F. Lutsenko, "Reaction of Tetraethyl Carbomethoxymethylene-1,1-diphosphonite with Alkyl Halides", Zhurnal Obshchei Khimii, Volume 48, No. 4 (1978), pp. 757-764. These references are hereby incorporated herein in their entirety.
A number of pathological conditions which can afflict humans and lower animals involve abnormal calcium and phosphate metabolism. Such conditions may be divided into two broad categories:
(1) Conditions which are characterized by anomolous mobilization of calcium and phosphate leading to general or specific bone loss, or excessively high calcium and phosphate levels in the fluids of the body, such as osteoporosis and Paget's disease. Such conditions are sometimes referred to herein as pathological hard tissue demineralizations. PA1 (2) Conditions which cause or result from deposition of calcium and phosphate anomolously in the body, such as arthritis. These conditions are sometimes referred to herein as pathological calcifications. PA1 (1) hydrogen; PA1 (2) halogen; more preferred are F or Cl; most preferred is F; PA1 (3) substituted and unsubstituted alkyl having the general structure: ##STR3## wherein n is an integer from 1 to about 10, preferably from 1 to about 5, more preferably n=1 or 2, and most preferably n=1; each R.sup.1 is independently selected to achieve chemically-stable moieties from the group consisting of hydrogen, halogen, lower alkyl, unsubstituted amino or the amide thereof derived from a carboxylic acid of a lower alkyl group, amino substituted with one lower alkyl group or the amide thereof derived from a carboxylic acid of a lower alkyl group, amino substituted independently with two lower alkyl groups, hydroxy or the ester thereof derived from a carboxylic acid of a lower alkyl group, --CO.sub.2 H or the pharmaceutically-acceptable salts thereof or the ester thereof derived from an alcohol of a lower alkyl group or the unsubstituted amide thereof or the amide thereof substituted with one or two lower alkyl groups, ether having a lower alkyl group, --PO.sub.3 H.sub.2 or the pharmaceutically-acceptable salts thereof, and nitro, or two R.sup.1 's on the same carbon atom are .dbd.O or .dbd.NR.sup.9 (where R is lower alkyl or may be hydrogen when there is another nitrogen atom attached to the same as the =NR.sup.9 moiety), or two R.sup.1 's on adjacent carbon atom carbon atoms may be replaced by an additional bond between the carbon atoms; or an R.sup.1 on the first carbon atom (from the right side of structure (2) hereinabove) and B (see structure (1) hereinabove) may be replaced by an additional bond; and Y is a substituent of alkyl as defined hereinbefore; (For the sake of chemical stability of the compounds of the present invention, R.sup.1 cannot be such that there is a halogen and an oxygen or sulfur or nitrogen singly bonded to the same carbon atom or such that two of an oxygen or sulfur or nitrogen are singly bonded to the same carbon atom); PA1 (4) Cycloalkyl having from about 4 to about 10 carbon atoms; more preferred are cycloalkyl having 5 or 6 carbon atoms; PA1 (5) Heterocycle having 5 or 6 atoms in the ring; more preferred are heterocycles having one or two nitrogen atoms in the ring, more preferred still are heterocycles having one nitrogen atom in the ring; most preferred are unsubstituted or substituted piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl; PA1 (6) unsubstituted and substituted phenyl; naphthyl; PA1 (7) unsubstituted and substituted 5 and 6 membered ring heteroaryls having one or two heteroatoms (especially nitrogen heteroatoms); most preferred is pyridinyl; PA1 (8) amine-containing moiety having the general structure: ##STR4## wherein m is an integer from 0 to about 10, preferably from 0 to about 5, more preferably 0 or 1, and most preferably m=0; R.sup.1 and Y are as described hereinbefore; and R.sup.2 is hydrogen, lower alkyl or acyl derived from a carboxylic acid of a lower alkyl; PA1 (9) oxygen-containing moiety having the general structure: ##STR5## wherein m is an integer from 0 to about 10, preferably from 0 to about 5, more preferably 0 or 1, and most preferably m=0; and R.sup.1 and Y are as described hereinbefore; and (10) sulfur-containing moiety having the general structure: ##STR6## wherein m is an integer from 0 to about 10, preferably from 0 to about 5, more preferably 0 or 1, and most preferably m=0; and R.sup.1 and Y are as described hereinbefore; PA1 (11) peptide-containing moiety having the general structure: ##STR7## wherein n is an integer from 1 to about 100, preferably from 1 to about 6; R.sup.5, each R.sup.6 and R.sup.7 are independently hydrogen or lower alkyl, preferably R.sup.5, each R.sup.6 and R.sup.7 are hydrogen; U and each V are independently unsubstituted or substituted lower alkyl (substituted such that moiety is chemically-stable), or R.sup.5 and U or each R.sup.6 and V, together with the included nitrogen atom to which they are bound, may form a five- or six-membered ring which is unsubstituted or substituted; or U may be nil; preferably U and each V or rings in which they are incorporated are moieties found in naturally-occurring amino acid moieties, i.e. lysine, leucine, isoleucine, valine, phenylalanine, arginine, histidine, methionine, alanine, aspartic acid, threonine, proline, glycine, serine, tyrosine, tryptophan, glutamine and cysteine. PA1 (a) unsubstituted or substituted cyclopropane-1-phosphono-1-alkylphosphinates having the general structure: ##STR45## (b) unsubstituted or substituted cyclobutane-1-phosphono-1-alkylphosphinates having the general structure: ##STR46## (c) unsubstituted or substituted cyclopentane-1-phosphono-1-alkylphosphinates having the general structure: ##STR47## (d) unsubstituted or substituted cyclopentene-1-phosphono-1-alkylphosphinates having the general structure: ##STR48## (e) unsubstituted or substituted cyclohexane-1-phosphono-1-alkylphosphinates having the general structure: ##STR49## (f) unsubstituted or substituted cyclohexene-1-phosphono-1-alkylphosphinates having the general structures: ##STR50## (g) unsubstituted or substituted cycloheptane-1-phosphono-1-alkylphosphinates having the general structure: ##STR51## (h) unsubstituted or substituted indan-2,2-phosphonoalkylphosphinates having the general structure: ##STR52## (i) unsubstituted or substituted hexahydroindan-2,2-phosphonoalkylphosphinates having the general structure: ##STR53## (j) unsubstituted or substituted octahydropyrindine-6,6-phosphonoalkylphosphinates having the general structures: ##STR54## (k) unsubstituted or substituted pyrrolidine-2-phosphono-2-alkylphosphinates and pyrrolidine-3-phosphono-3-alkylphosphinates having the general structures: ##STR55## (l) unsubstituted or substituted piperidine-2-phosphono-2-alkylphosphinates, piperidine-3-phosphono-3-alkylphosphinates and piperidine-4-phosphono-4-alkylphosphinates having the general structures: ##STR56## (m) unsubstituted or substituted octahydro[2,3-b]- and [2,3-c]pyrrolopyridine-5-phosphono-5-alkylphosphinates having the general structures: ##STR57## (n) unsubstituted or substituted octahydro[2,3-b]- and [2,3-c]furanpyridine-5-phosphono-5-alkylphosphinates having the general structures: ##STR58##
A variety of polyphosphonic acid derivatives, especially diphosphonic acid derivatives, have been proposed for use in the treatment and prophylaxis of diseases involving abnormal calcium and phosphate metabolism. For example, polyphosphonic acid compounds are disclosed in U.S. Pat. No. 3,683,080, issued Aug. 8, 1972 to Francis; U.S. Pat. No. 4,330,537, issued Oct. 28, 1980 to Francis; U.S. Pat. No. 4,267,108, issued May 12, 1981 to Blum et al.; and Francis and Martodam, "Chemical, Biochemical, and Medicinal Properties of the Diphosphonates" in The Role of Phosphonates in Living Systems (CRC Press; Hilderbrand, Editor), pp. 55-96(1983); the disclosure of all these publications being incorporated herein by reference.
Certain substituted phosphinic acids are disclosed to be useful for the treatment of inflammatory conditions, including arthritis, in U.S. Pat. No. 4,469,686 issued to Andrews on Sep. 4, 1984.
In spite of the above and much other research into the use of polyphosphonates to treat bone-metabolism diseases, there continues to be a need for new bone-active agents. The object of the present invention is therefore to provide a new class of bone-active compounds. It is a further object of the present invention to provide bone-active agents having low toxicity. Furthermore, an object of the present invention is to provide new bone-active compounds with favorable therapeutic indices. It is a further object of the present invention to provide pharmaceutical compositions useful for the treatment and prophylaxis of abnormal calcium and phosphate metabolism. In addition, it is an object of the present invention to provide methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism in humans or lower animals.
These and other objects of the present invention will be apparent from the detailed disclosure of the present invention provided hereinafter.